John Tamkun

Professor of MCD Biology B.A., University of South Florida Ph.D., Massachusetts Institute of Technology Postdoctorate, University of Colorado, Boulder

Regulation of Chromatin Structure and Gene Expression

Nucleosomes and other components of chromatin repress transcription by blocking the access of transcription factors and other proteins to DNA. Eukaryotic cells use two general mechanisms to regulate chromatin repression: the covalent modification of nucleosomal histones and ATP-dependent chromatin remodeling.

The site-specific acetylation, phosphorylation or methylation of histone tails alters the ability of nucleosomes to interact with structural or regulatory proteins. As a result, histone-modifying enzymes can have profound effects on chromatin structure and gene expression. Chromatin-remodeling reactions are catalyzed by large protein complexes that use the energy of ATP hydrolysis to alter the structure or positioning of nucleosomes. By modulating the access of proteins to DNA in the context of chromatin, chromatin remodeling complexes play important roles in a variety of nuclear processes, including transcriptional activation and repression; the maintenance of higher-order chromatin structure; and DNA replication, repair and recombination.

To fully understand the mechanism of action of chromatin remodeling complexes, it will be necessary to determine how their activities are regulated; how they are targeted to specific genes; and how they interact with histone-modifying enzymes and other regulatory proteins to modulate chromatin structure and transcription. Our laboratory uses the fruit fly Drosophila melanogaster as a model organism to address these important issues.

We use a combination of genetic, biochemical and molecular approaches to study Drosophila chromatin-remodeling complexes. Much of our current research is focused on their roles in transcriptional regulation and the maintenance of higher order chromatin structure. We also study the regulation of chromatin-remodeling by acetylation and other post-translational modifications of chromatin. Finally, our laboratory has a long-standing interest in the role of chromatin and chromatin remodeling complexes in cell fate specification.

Highly conserved counterparts of Drosophila chromatin remodeling factors are present in humans. Mutations in genes encoding subunits of human chromatin-remodeling complexes are associated with cancer and other diseases. Our studies of Drosophila chromatin-remodeling factors are therefore directly relevant to human health.

Selected Publications
Kingston, R.E. and Tamkun, J.W. (2006) Transcriptional regulation by Trithorax group proteins, in Epigenetics (edited by C.D. Allis, T. Jenuwein and D. Reinberg) Cold Spring Harbor Laboratory Press, in press.

Armstrong, J. A., Sperling, A. S., Deuring, R., Manning, L., Moseley, S. L., Papoulas, O., Piatek, C. I., Doe, C. Q. and Tamkun, J. W. (2005). Genetic screens for enhancers of brahma reveal functional interactions between the BRM chromatin-remodeling complex and the delta-notch signal transduction pathway in Drosophila. Genetics 170, 1761-74.

Srinivasan, S., Armstrong, J. A., Deuring, R., Dahlsveen, I. K., McNeill, H., Tamkun, J. W. (2005) The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II. Development 32: 1623-35

Corona DF. and Tamkun JW. (2004) Multiple roles for ISWI in transcription, chromosome organization and DNA replication. Biochem Biophys Acta 1677:113-9.

Corona, D.F.V, ,Armstrong, J.A., and Tamkun, J.W. (2003) Genetic and Cytological Analysis of Drosophila Chromatin-remodeling Factors , in Methods in Enzymology, volume 377, Chromatin and Chromatin Remodeling Enzymes, Part C (edited by C. Wu and C.D. Allis).

Stillman, D.J. and Tamkun, J.W.. (2003) Chromosomes and expression mechanisms. Common themes in gene expression from the nucleosome to the whole organism. Current Opinion in Genetics and Development 13:105-7 (editorial overview).

Armstrong, J.A., Papoulas, O., Daubresse, G., Sperling, A.S., Lis, J.T., Scott, M.P., and Tamkun, J.W. (2002) The Drosophila BRM complex facilitates global transcription by RNA polymerase II. EMBO Journal 21: 5245-54.

Moshkin, Y.M., Armstrong, J.A., Maeda, R.K., Tamkun, J.W., Verrijzer, C.P., Kennison, J.A., and Karch, F. (2002) Histone chaperone ASF1 cooperates with the Brahma chromatin-remodelling machinery. Genes and Development 16: 2621-6.

Simon, J. A., and Tamkun, J. W. (2002). Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Current Opinion in Genetics and Development 12, 210-218.

Corona, D. F., Clapier, C. R., Becker, P. B., and Tamkun, J. W. (2002). Modulation of ISWI function by site-specific histone acetylation. EMBO Reports 3, 242-247.

Papoulas, O., Daubresse, G., Armstrong, J. A., Jin, J., Scott, M. P., and Tamkun, J. W. (2001). The HMG-domain protein BAP111 is important for the function of the BRM chromatin-remodeling complex in vivo. Proc Natl Acad Sci U S A 98, 5728-5733.

Mollaaghababa, R., Sipos, L., Tiong, S. Y., Papoulas, O., Armstrong, J. A., Tamkun, J. W., and Bender, W. (2001). Mutations in Drosophila heat shock cognate 4 are enhancers of Polycomb. Proc Natl Acad Sci U S A 98, 3958-3963.

Ruhf, M.L., Braun, A., Papoulas, O., Tamkun, J.W., Randsholt, N. and M. Meister. The domino gene of Drosophila encodes novel members of the SWI2/SNF2 family of DNA-dependent ATPases which interact with Polycomb-group proteins. 2001 Development 128: 1429-1441.

Corona, D.F.V., Eberharter, A., Budde, A., Deuring, R., Ferrari, S., Varga-Weisz, P., Wilm, M., Tamkun, J. and Becker, P.B. 2000. Two histone fold proteins, CHRAC-14 and CHRAC-16, are developmentally regulated subunits of CHRAC. EMBO Journal 19: 3049-3059.

Deuring, R., Fanti, L., Armstrong, J.A., Sarte, M., Papoulas, O., Prestel, M., Daubresse, G., Verardo, M., Moseley, S.L., Berloco, M., Tsukiyama, T., Wu, C., Pimpinelli, S., and Tamkun, J.W. 2000. The ISWI chromatin remodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Molecular Cell 5, 355-365.

Corona, D. F., Langst, G., Clapier, C. R., Bonte, E. J., Ferrari, S., Tamkun, J. W., and Becker, P. B. 1999. ISWI is an ATP-dependent nucleosome remodeling factor. Molecular Cell 3, 239-45.

Daubresse, G., Deuring, R., Moore, L., Papoulas, O., Zakrajsek, I., Waldrip, W. R., Scott, M. P., Kennison, J. A., and Tamkun, J. W. 1999. The Drosophila kismet gene is related to chromatin-remodeling factors and is required for both segmentation and segment identity. Development 126, 1175-87.